Melanomas are caused generally by the exposure of skin to sunlight. Persons of fair complexion have the greatest risk especially those who develop moles.
Melanomas originate from a change in normal skin cells, melanocytes, which produce the brown pigment melanin we recognise as tan. Moles and freckles result from areas of the skin with many melanocytes.
The influence of light on melanocytes is one way by which they can be changed to grow and divide differently, possibly causing a melanoma. The melanomas may be malignant, spreading to other parts of the body. Melanomas which do not spread are called benign.
Although melanomas normally form on exposed skin they can start in places such as the mouth or bowel.
Melanomas grow in size and need to be surgically removed before they spread and invade other parts of the body. If the melanomas spread to the inner organs, removal and treatment is more difficult and chemotherapy or radiotherapy need to be employed.
It has been hypothesised that carotenoids and in particular beta-carotene may reduce the risk of breast, lung, colon, prostate and cervical cancer, heart disease and stroke and may retard macular degeneration. In this respect, one hypothesis is that in mammals beta-carotene is converted to vitamin A and vitamin A analogues or retinoids (see Moon RC: Comparative aspects of carotenoids and retinoids as chemopreventive agents for cancer. J Nutr 119:127-134, 1989). It is this pro-vitamin A activity and the ability to prevent oxidative damage that has made carotenoids and in particular beta-carotene a compound of interest in chemopreventive studies. For instance, anti-oxidants are used, amongst other things, to quench free radicals that are by-products of normal metabolism in cells.
Beta-carotene has also been used in the treatment of erythropoietic protoporphyria (EPP). EPP is a genetic disease causing an inadequacy in the metabolism of porphyrin compounds. It results in a rapid blistering of the skin on exposure to sunlight.
When considering the use of carotenoid compositions for human application an immediate difficulty arises as a result of the nature of carotenoids.
Carotenoids are lipophyllic and therefore not soluble in water in useful quantities. It is believed that they are transported in the bloodstream as low density lipoproteins.
The current principal means by which carotenoids are introduced into the body is orally. However, this method is often unsatisfactory because the poor absorption of the carotenoid composition by the alimentary canal limits the concentrations in the blood which can be achieved. Further, there will be a substantial delay before a required level of carotenoids in the bloodstream or a specific organ is reached. Sometimes the required level cannot be reached as certain individuals do not absorb carotenoids very well, especially beta-carotene. There is about a tenfold difference in the ability of human individuals to absorb beta-carotene. There have been over 500 carotenoids isolated, but only approximately 15 have been shown to occur in the bloodstream.
Physicians often seek to administer compounds by injection or by intravenous drip rather than oral ingestion. However, because of the virtual water insolubility of carotenoid compositions it is very difficult to administer them either by injection or intravenously. The compound must be made dispersible in an aqueous base so that it is available to the body's cells. In this regard, the base must be compatible with, for example, the bloodstream or lymph, and the material must be prepared in a biologically sterile form. The base must itself be non-toxic to the human cells.
To date several in vitro studies have taken place to determine the effect of beta-carotene on normal and transformed cell types using solvents to solubilise the beta-carotene such as tetrahydrofuran, butanol, chloroform, hexane, dimethylsulfoxide, ethanol or in a liposome micelle. Previous liposome preparations have shown toxicity in cell line cultures as well as being limited in application (see Bertram J S, Pung A, Churley M, et al: Diverse carotenoids protect against chemically induced neoplastic transformation. Carcinogenesis 12:671-678, 1991; Hazuka M B, Prasad-Edwards J, Newman F, et al: Beta-carotene induces morphological differentiation and decreases adenylate cyclase activity in melanoma cells in culture. J Am Coll Nutr 9:143-149, 1990; Schultz T D, Chew B P, Seaman W R, et al: Inhibitory effect of conjugated dienoic derivatives of linoleic acid and beta-carotene on the in vitro growth of human cancer cells. Canc Letters 63:125-133, 1992; Schwartz J L, Shklar G: The selective cytotoxic effect of carotenoids and a-tocopherol on human cancer cell lines in vitro. J Oral Maxillofac Surg 50:367-373, 1992; Schwartz J L, Tanaka J, Khandekar V, et al: Beta-Carotene and/or Vitamin E as modulators of alkylating agents in SCC-25 human squamous carcinoma cells. Canc Chemother Pharmacol 29:207-213, 1992; Zhang L-X, Cooney R V, Bertram J S: Carotenoids enhance gap junctional communication and inhibit lipid peroxidation in C3H/10T1/2 cells: relationship to their cancer chemopreventive action. Carcinogenesis 12:2109-2114, 1991; and Zhang L-X, Cooney R V, Bertram J S: Carotenoids up-regulate connexin 43 gene expression independent of their provitamin A or antioxidant properties. Canc Res 52:5707-5712, 1992). These solvents have been found to have a toxic effect which is dose dependent. These solvents are also incompatible with human blood or lymph for the purposes of intravenous or injectable preparations.
Accordingly, investigations were carried out to develop a carotenoid composition which could be accepted by the human body and other animals and display efficacy in the treatment of melanomas.